Effect of nisoldipine on priming and activation of the human neutrophil respiratory burst.
Nisoldipine inhibits calcium (Ca++) influx in human neutrophils: Preincubation with the dihydropyridine, nisoldipine (1.5 microM) resulted in a 30% decrease in [45]Ca++ influx during formyl-methionine-leucine-phenylalanine (FMLP) stimulation in primed as well as resting cells. Although the drug does not inhibit Ca++ dependent effector functions elicited by FMLP, e.g. superoxide (O2-) production, it inhibits FMLP priming, a phenomenon that is independent of extracellular Ca++. Nisoldipine exhibited a narrow dose response with an ED50 of ca. 1 microM and total inhibition of primed O2- response at 1.5 microM. Nisoldipine (1.5 microM) also abolished the incremental rise of Ca++i in primed neutrophils stimulated with FMLP. The dissociation of nisoldipine inhibitory effects on cell effector function and Ca++ transport were corroborated in studies with neutrophils stimulated with influenza virus and phorbol myristate acetate (PMA), stimuli which do not exhibit an extracellular Ca(++)-dependence in their elicited responses. Unlike in FMLP-stimulated cells, nisoldipine reduced influenza virus and PMA initiated respiratory burst, indicating that this drug has inhibitory effects on neutrophil function independent of its effect on Ca++ metabolism. Possible sites of action are postulated at phospholipase A2 or calmodulin-regulated activities. Caution is thus required in interpreting the effects of dihydropyridine on cell function, when the drug is used at micromolar concentration.
Karnad
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William B. Castle Hematology Research Laboratory, Boston City Hospital, MA.
Hartshorn
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KL
Tauber
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D001711:Biotransformation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D015737:Nisoldipine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015737:Nisoldipine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium